Pathogenesis of vascular leak in dengue virus infection

Abstract

Endothelial dysfunction leading to vascular leak is the hallmark of severe dengue. Vascular leak typically becomes clinically evident 3-6 days after the onset of illness, which is known as the critical phase. This critical phase follows the period of peak viraemia, and lasts for 24-48 hr and usually shows rapid and complete reversal, suggesting that it is likely to occur as a result of inflammatory mediators, rather than infection of the endothelium. Cytokines such as tumour necrosis factor-α, which are known to be elevated in the critical phase of dengue, are likely to be contributing factors. Dengue NS1, a soluble viral protein, has also been shown to disrupt the endothelial glycocalyx and thus contribute to vascular leak, although there appears to be a discordance between the timing of NS1 antigenaemia and occurrence of vascular leak. In addition, many inflammatory lipid mediators are elevated in acute dengue viral infection such as platelet activating factor (PAF) and leukotrienes. Furthermore, many other inflammatory mediators such as vascular endothelial growth factor and angiopoietin-2 have been shown to be elevated in patients with dengue haemorrhagic fever, exerting their action in part by inducing the activity of phospholipases, which have diverse inflammatory effects including generation of PAF. Platelets have also been shown to significantly contribute to endothelial dysfunction by production of interleukin-1β through activation of the NLRP3 inflammasome and also by inducing production of inflammatory cytokines by monocytes. Drugs that block down-stream immunological mediator pathways such as PAF may also be beneficial in the treatment of severe disease.

Keywords: NS1 antigen; dengue; lipid mediators; platelet activating factor; vascular leak.

Figure 1

Model of endothelial dysfunction in dengue infection. Cytokines and tumour necrosis factor‐α (TNF‐α) produced by dengue virus (DENV) ‐infected monocytes, dendritic cells (DCs) and macrophages possibly cause endothelial activation and also activate nuclear factor‐κB (NF‐κB) to induce platelet‐activating factor (PAF) production. LPS present in the blood by possible microbial translocation amplifies this effect and also induces PAF production from these cells. Vascular endothelial growth factor (VEGF) produced by mast cells and other cells act on secretory phospholipase A2 (sPLA2) to induce production of PAF and mast cells are also a possible source of sPLA2, which leads to PAF production. Platelets, which are also directly infected by the DENV, produce many cytokines by forming platelet monocyte aggregates. Platelet‐derived microparticles, are an important source of interleukin‐1β (IL‐1β), which are produced by activation of the NLRP3 inflammasome. NS1 could also act through Toll‐like receptor 4 (TLR4) inducing phospholipases to generate PAF from phospholipids and also induce production of many inflammatory cytokines, which contribute to the ‘cytokine storm’. Ang‐2 produced by endothelial activation also in turn activated sPLA2 to induce PAF production. Dengue NS1 hexamers bind to the endothelial glycocalyx, resulting in loss of sialic acid. NS1 also leads to the cleavage of heparan sulphate from the endothelial glycocalyx.